PubMed

Related Articles Untargeted liquid chromatography coupled with mass spectrometry reveals metabolic changes in nitrogen-deficient Isatis indigotica Fortune. Phytochemistry. 2019 Jul 04;166:112058 Authors: Cao YW, Qu RJ, Miao YJ, Tang XQ, Zhou Y, Wang L, Geng L Abstract Isatis indigotica Fortune is a popular herb in traditional Chinese medicine, and various types of metabolites are the basis for its pharmacological efficacy. The biosynthesis and accumulation of these metabolites are closely linked to nitrogen availability; the benefits of low nitrogen application on the environment and herb quality are increasingly prominent. To analyze metabolic changes in the leaves and roots of I.indigotica in nitrogen deficiency conditions, and to identify the pathways and metabolites induced by low nitrogen availability, we used untargeted liquid chromatography coupled with mass spectrometry (UHPLC-TripleTOF) to obtain metabolomics profiling of I.indigotica under two N-deficiency treatments (0 kg/hm2; 337.5 kg/hm2) and normal nitrogen treatment (675 kg/hm2). A total of 447 metabolites were annotated. Principal component analysis separated the three nitrogen treatments. A greater diversity of metabolites was observed in roots than in leaves under N-deficiency treatments, suggesting that roots have a more important function in low N tolerance. Differential metabolites were mainly enriched in purine metabolism, phenylpropanoid biosynthesis, the shikimate pathway, tryptophan metabolism, and flavonoid biosynthesis that notably induced only in leaves in low nitrogen stress. Moderate N-deficiency benefits carbohydrate accumulation, whereas accumulation of most amino acids decreases. Uniquely, L-tryptophan was maintained at a high concentration in N-deficiency conditions. Low nitrogen stress induced the accumulation of some specialized metabolites (matairesinol, dictamnine, 5-hydroxyindoleacetate (serotonin) in roots and vitexin, xanthohumol, sinapyl alcohol in leaves). N-deficiency also increased the accumulation of adenosine and quality indicators of I.indigotica (indirubin-indigo, epigoitrin and anthranilic acid) in a certain degree. Our findings showed that nitrogen deficiency modified roots and leaves conditions of I.indigotica, affecting both the primary and secondary metabolism. Moderate nitrogen reduction was beneficial to the accumulation of active ingredients. Our methods and analysis are expected to provide an insight regarding the diversity of metabolites and regulation of their synthesis in low nitrogen application, and better investigate the nitrogen deficiency effect on I.indigotica. PMID: 31280093 [PubMed - as supplied by publisher]

Related Articles Application of metabolomics for unveiling the therapeutic role of traditional Chinese medicine in metabolic diseases. J Ethnopharmacol. 2019 Jul 04;:112057 Authors: Wu G, Zhang W, Li H Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Traditional medicine has been practiced for thousands of years in China and some Asian countries. Traditional Chinese Medicine (TCM) is characterized as multi-component and multiple targets in disease therapy, and it is a great challenge for elucidating the mechanisms of TCM. AIM OF THE REVIEW: Comprehensively summarize the application of metabolomics in biomarker discovery, stratification of TCM syndromes, and mechanism underlying TCM therapy on metabolic diseases. METHODS: This review systemically searched the publications with key words such as metabolomics, traditional Chinese medicine, metabolic diseases, obesity, cardiovascular disease, diabetes mellitus in "Title OR Abstract" in major databases including PubMed, the Web of Science, Google Scholar, Science Direct, CNKI from 2010 to 2019. RESULTS: A total of 135 papers was searched and included in this review. An overview of articles indicated that metabolic characteristics may be a hallmark of different syndromes/models of metabolic diseases, which provides a new perspective for disease diagnosis and therapeutic optimization. Moreover, TCM treatment has significantly altered the metabolic perturbations associated with metabolic diseases, which may be an important mechanism for the therapeutic effect of TCM. CONCLUSIONS: Until now, many metabolites and differential biomarkers related to the pathogenesis of metabolic diseases and TCM therapy have been discovered through metabolomics research. Unfortunately, the biological role and mechanism of disease-related metabolites were largely unclarified so far, which warrants further investigation. PMID: 31279867 [PubMed - as supplied by publisher]

Related Articles A 1H-NMR based study of hemolymph metabonomics in different resistant silkworms, Bombyx mori (Lepidotera), after BmNPV inoculation. J Insect Physiol. 2019 Jul 04;:103911 Authors: Wang XY, Shao ZM, Zhang YJ, Vu TT, Wu YC, Xu JP, Deng MJ Abstract Bombyx mori nucleopolyhedrovirus (BmNPV) is a primary silkworm pathogen, and the molecular mechanism of silkworm defense to BmNPV infection is still unclear. Herein, comparative metabolomics was adopted to analyze the variations in the hemolymph metabolites of different resistant silkworm strains following BmNPV inoculation using a 1H-NMR method. Trehalose, as an instant source of energy, plays a crucial role in the response to pathogen infections in insects. The level of trehalose was persistently upregulated in the hemolymph of the resistant silkworm strain YeA following infection with BmNPV, compared to that of the susceptible strain YeB, indicating that trehalose metabolism plays a vital role in the response to BmNPV infection. The significant upregulation of TCA cycle relevant metabolites, including malate, fumarate, citrate, succinate, and α-ketoglutarate, was identified at 0 h, 12 h, 48 h, and 96 h post-infection in YeA hemolymph, whereas a significant upregulation in YeB hemolymph was only detected at an early stage of infection (0 h-24 h). The expression level of selected key metabolic enzymes, determined using RT-qPCR, validated the differences in trehalose and TCA cycle relevant metabolite levels. The variations in branched-chain amino acid (BCAA) pathway relevant metabolites in resistant silkworm strains following BmNPV infection showed a regular undulation at different times after infection. A significant accumulation of phenylalanine and tyrosine was observed in YeA following BmNPV infection compared to YeB. The glycolysis and gluconeogenesis pathways showed a relatively low activity in YeA following BmNPV infection. Moreover, the levels of other metabolites related to fat metabolism, transamination, energy metabolism, and glycometabolism, such as glycine, threonine, glutamine, and glutamate, were unstable in the two silkworm strains following BmNPV infection. Thus, our study provides an overview of the metabolic response of the silkworm in response to BmNPV infection, which lays the foundation for clarifying the mechanism of silkworm resistance to BmNPV infection. PMID: 31279633 [PubMed - as supplied by publisher]

Related Articles Metabolomics reveals plausible interactive effects between dairy product consumption and metabolic syndrome in humans. Clin Nutr. 2019 Jun 26;: Authors: Capel F, Bongard V, Malpuech-Brugère C, Karoly E, Michelotti GA, Rigaudière JP, Jouve C, Ferrières J, Marmonier C, Sébédio JL Abstract BACKGROUND & AIMS: Metabolic syndrome (MetS) induces major disturbances in plasma metabolome, reflecting abnormalities of several metabolic pathways. Recent evidences have demonstrated that the consumption of dairy products may protect from MetS, but the mechanisms remains unknown. The present study aimed at identify how the consumption of different types of dairy products could modify the changes in plasma metabolome during MetS. METHODS: In this observational study, we analyzed how the consumption of dairy products could modify the perturbations in the plasma metabolome induced by MetS in a sample of 298 participants (61 with MetS) from the French MONA LISA survey. Metabolomic profiling was analyzed with UPLC-MS/MS. RESULTS: Subjects with MetS exhibited major changes in plasma metabolome. Significant differences in plasma levels of branched chain amino acids, gamma-glutamyl amino acids, and metabolites from arginine and proline metabolism were observed between healthy control and Mets subjects. Plasma levels of many lipid species were increased with MetS (mono- and diacylglycerols, eicosanoids, lysophospholipids and lysoplasmalogens), with corresponding decreases in short chain fatty acids and plasmalogens. The consumption of dairy products, notably with a low fat content (milk and fresh dairy products), altered metabolite profiles in plasma from MetS subjects. Specifically, increasing consumption of dairy products promoted accumulation of plasma C15:0 fatty acid and was inversely associated to some circulating lysophospholipids, sphingolipids, gamma-glutamyl amino acids, leukotriene B4 and lysoplasmalogens. CONCLUSIONS: the consumption of low fat dairy products could mitigate some of the variations induced by MetS. PMID: 31279616 [PubMed - as supplied by publisher]

Related Articles Genetic variance of metabolomic features and their relationship with body weight and body weight gain in Holstein cattle. J Anim Sci. 2019 Jul 05;: Authors: Aliakbari A, Ehsani A, Vaez Torshizi R, Løvendahl P, Esfandyari H, Jensen J, Sarup P Abstract In recent years, metabolomics has been used to clarify the biology underlying biological samples. In the field of animal breeding, investigating the magnitude of genetic control on the metabolomic profiles of animals and their relationships with quantitative traits adds valuable information to animal improvement schemes. In this study, we analyzed metabolomic features (MFs) extracted from the metabolomic profiles of 843 male Holstein calves. The metabolomic profiles were obtained using nuclear magnetic resonance (NMR) spectroscopy. We investigated two alternative methods to control for peak shifts in the NMR spectra, binning and aligning, to determine which approach was the most efficient for assessing genetic variance. Series of univariate analyses were implemented to elucidate the heritability of each MF. Furthermore, records on body weight (BW) and average daily gains from 154 to 294 days of age (ADG154-294), 294 to 336 days of age (ADG294-336), and 154 to 336 days of age (ADG154-336) were used in a series of bivariate analyses to establish the genetic and phenotypic correlations with MFs. Bivariate analyses were only performed for MFs that had a heritability significantly different from zero. The heritabilities obtained in the univariate analyses for the MFs in the binned dataset were low (< 0.2). In contrast, in the aligned dataset, we obtained moderate heritability (0.2 to 0.5) for 3.5% of MFs and high heritability (more than 0.5) for 1% of MFs. The bivariate analyses showed that ~12 %, ~3 %, ~9 %, and ~9 % of MFs had significant additive genetic correlations with BW, ADG154-294, ADG294-336, and ADG154-336, respectively. In all of the bivariate analyses, the percentage of significant additive genetic correlations was higher than the percentage of significant phenotypic correlations of the corresponding trait. Our results provided insights into the influence of the underlying genetic mechanisms on MFs. Further investigations in this field are needed for better understanding of the genetic relationship among the MFs and quantitative traits. PMID: 31278866 [PubMed - as supplied by publisher]

Related Articles Systems Genetics for Evolutionary Studies. Methods Mol Biol. 2019;1910:635-652 Authors: Prins P, Smant G, Arends D, Mulligan MK, Williams RW, Jansen RC Abstract Systems genetics combines high-throughput genomic data with genetic analysis. In this chapter, we review and discuss application of systems genetics in the context of evolutionary studies, in which high-throughput molecular technologies are being combined with quantitative trait locus (QTL) analysis in segregating populations.The recent explosion of high-throughput data-measuring thousands of RNAs, proteins, and metabolites, using deep sequencing, mass spectrometry, chromatin, methyl-DNA immunoprecipitation, etc.-allows the dissection of causes of genetic variation underlying quantitative phenotypes of all types. To deal with the sheer amount of data, powerful statistical tools are needed to analyze multidimensional relationships and to extract valuable information and new modes and mechanisms of changes both within and between species. In the context of evolutionary computational biology, a well-designed experiment and the right population can help dissect complex traits likely to be under selection using proven statistical methods for associating phenotypic variation with chromosomal locations.Recent evolutionary expression QTL (eQTL) studies focus on gene expression adaptations, mapping the gene expression landscape, and, tentatively, define networks of transcripts and proteins that are jointly modulated sets of eQTL networks. Here, we discuss the possibility of introducing an evolutionary "prior" in the form of gene families displaying evidence of positive selection, and using that prior in the context of an eQTL experiment for elucidating host-pathogen protein-protein interactions.Here we review one exemplar evolutionairy eQTL experiment and discuss experimental design, choice of platforms, analysis methods, scope, and interpretation of results. In brief we highlight how eQTL are defined; how they are used to assemble interacting and causally connected networks of RNAs, proteins, and metabolites; and how some QTLs can be efficiently converted to reasonably well-defined sequence variants. PMID: 31278680 [PubMed - in process]

Related Articles MCEE 2.0: more options and enhanced performance. Anal Bioanal Chem. 2019 Jul 05;: Authors: Li Y, Zheng X, Liang D, Zhao A, Jia W, Chen T Abstract A confounding factor is an unstudied factor that affects one or more of the variables that are being studied in an investigation, so the presence of a confounder may lead to inaccurate or biased results. It is well recognized that physiological and environmental factors such as race, diet, age, gender, blood pressure, and diurnal cycle affect mammalian metabolism. To eliminate the noise introduced by confounders into metabolomics studies, a GUI-based method denoted metabolic confounding effect elimination (MCEE) was developed and has since been applied successfully in a wide range of metabolomics studies. To keep up with recent developments in computational metabolomics and a growing number of user requests, an upgraded version of MCEE with more options and enhanced performance was designed and developed. Besides the generalized linear model (GLM) method, a multivariate method for selecting affected metabolites-canonical correlation analysis (CCA)-was introduced, which accounts for complicated correlations and collinearity within the metabolome. Multiple confounders are acceptable and can be identified and processed separately or simultaneously. The effectiveness of this new version of MCEE as well as the pros and cons of the two methodological options were examined using three simulated data sets (a basic model, a model with different sample size ratios, and a sparse model) and two real-world data sets (a human type 2 diabetes mellitus data set and a human arthritis data set). As well as presenting the results of this examination of the new version of MCEE, some instructions on appropriate method selection and parameter setting are provided here. The freely available MATLAB code for MCEE with a GUI has also been updated accordingly at https://github.com/chentianlu/MCEE-2.0 . Graphical abstract. PMID: 31278548 [PubMed - as supplied by publisher]

Related Articles Erythrocyte Adenosine A2B Receptor-Mediated AMPK Activation: A Missing Component Counteracting CKD by Promoting Oxygen Delivery. J Am Soc Nephrol. 2019 Jul 05;: Authors: Peng Z, Luo R, Xie T, Zhang W, Liu H, Wang W, Tao L, Kellems RE, Xia Y Abstract BACKGROUND: Oxygen deprivation or hypoxia in the kidney drives CKD and contributes to end organ damage. The erythrocyte's role in delivery of oxygen (O2) is regulated by hypoxia, but the effects of CKD are unknown. METHODS: We screened all of the metabolites in the whole blood of mice infused with angiotensin II (Ang II) at 140 ng/kg per minute up to 14 days to simulate CKD and compared their metabolites with those from untreated mice. Mice lacking a receptor on their erythrocytes called ADORA2B, which increases O2 delivery, and patients with CKD were studied to assess the role of ADORA2B-mediated O2 delivery in CKD. RESULTS: Untargeted metabolomics showed increased production of 2,3-biphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite promoting O2 delivery, in mice given Ang II to induce CKD. Genetic studies in mice revealed that erythrocyte ADORA2B signaling leads to AMPK-stimulated activation of BPG mutase, promoting 2,3-BPG production and O2 delivery to counteract kidney hypoxia, tissue damage, and disease progression in Ang II-induced CKD. Enhancing AMPK activation in mice offset kidney hypoxia by triggering 2,3-BPG production and O2 delivery. Patients with CKD had higher 2,3-BPG levels, AMPK activity, and O2 delivery in their erythrocytes compared with controls. Changes were proportional to disease severity, suggesting a protective effect. CONCLUSIONS: Mouse and human evidence reveals that ADORA2B-AMPK signaling cascade-induced 2,3-BPG production promotes O2 delivery by erythrocytes to counteract kidney hypoxia and progression of CKD. These findings pave a way to novel therapeutic avenues in CKD targeting this pathway. PMID: 31278195 [PubMed - as supplied by publisher]

Related Articles Leveraging -omics for asthma endotyping. J Allergy Clin Immunol. 2019 Jul;144(1):13-23 Authors: Tyler SR, Bunyavanich S Abstract Asthma is a highly heterogeneous disease, often manifesting with wheeze, dyspnea, chest tightness, and cough as prominent symptoms. The eliciting factors, natural history, underlying molecular biology, and clinical management of asthma vary highly among affected subjects. Because of this variation, many efforts have gone into subtyping asthma. Endotypes are subtypes of disease based on distinct pathophysiologic mechanisms. Endotypes can be clinically useful because they organize our mechanistic understanding of heterogeneous diseases and can direct treatment toward modalities that are likely to be the most effective. Asthma endotyping can be shaped by clinical features, laboratory parameters, and/or -omics approaches. We discuss the application of -omics approaches, including transcriptomics, epigenomics, microbiomics, metabolomics, and proteomics, to asthma endotyping. -Omics approaches have provided supporting evidence for many existing endotyping paradigms and also suggested novel ways to conceptualize asthma endotypes. Although endotypes based on single -omics approaches are relatively common, their integrated multi-omics application to asthma endotyping has been more limited thus far. We discuss paths forward to integrate multi-omics with clinical features and laboratory parameters to achieve the goal of precise asthma endotypes. PMID: 31277743 [PubMed - in process]

Related Articles Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure. Cardiovasc Diabetol. 2019 Jul 05;18(1):86 Authors: Uddin GM, Zhang L, Shah S, Fukushima A, Wagg CS, Gopal K, Al Batran R, Pherwani S, Ho KL, Boisvenue J, Karwi QG, Altamimi T, Wishart DS, Dyck JRB, Ussher JR, Oudit GY, Lopaschuk GD Abstract BACKGROUND: Branched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. We, therefore, determined if cardiac BCAA accumulation occurs in patients with dilated cardiomyopathy (DCM), due to an impaired catabolism of BCAA, and if stimulating cardiac BCAA oxidation can improve cardiac function in mice with heart failure. METHOD: For human cohorts of DCM and control, both male and female patients of ages between 22 and 66 years were recruited with informed consent from University of Alberta hospital. Left ventricular biopsies were obtained at the time of transplantation. Control biopsies were obtained from non-transplanted donor hearts without heart disease history. To determine if stimulating BCAA catabolism could lessen the severity of heart failure, C57BL/6J mice subjected to a transverse aortic constriction (TAC) were treated between 1 to 4-week post-surgery with either vehicle or a stimulator of BCAA oxidation (BT2, 40 mg/kg/day). RESULT: Echocardiographic data showed a reduction in ejection fraction (54.3 ± 2.3 to 22.3 ± 2.2%) and an enhanced formation of cardiac fibrosis in DCM patients when compared to the control patients. Cardiac BCAA levels were dramatically elevated in left ventricular samples of patients with DCM. Hearts from DCM patients showed a blunted insulin signalling pathway, as indicated by an increase in P-IRS1ser636/639 and its upstream modulator P-p70S6K, but a decrease in its downstream modulators P-AKT ser473 and in P-GSK3β ser9. Cardiac BCAA oxidation in isolated working hearts was significantly enhanced by BT2, compared to vehicle, following either acute or chronic treatment. Treatment of TAC mice with BT2 significantly improved cardiac function in both sham and TAC mice (63.0 ± 1.8 and 56.9 ± 3.8% ejection fraction respectively). Furthermore, P-BCKDH and BCKDK expression was significantly decreased in the BT2 treated groups. CONCLUSION: We conclude that impaired cardiac BCAA catabolism and insulin signaling occur in human heart failure, while enhancing BCAA oxidation can improve cardiac function in the failing mouse heart. PMID: 31277657 [PubMed - in process]

Related Articles Improving MetFrag with statistical learning of fragment annotations. BMC Bioinformatics. 2019 Jul 05;20(1):376 Authors: Ruttkies C, Neumann S, Posch S Abstract BACKGROUND: Molecule identification is a crucial step in metabolomics and environmental sciences. Besides in silico fragmentation, as performed by MetFrag, also machine learning and statistical methods evolved, showing an improvement in molecule annotation based on MS/MS data. In this work we present a new statistical scoring method where annotations of m/z fragment peaks to fragment-structures are learned in a training step. Based on a Bayesian model, two additional scoring terms are integrated into the new MetFrag2.4.5 and evaluated on the test data set of the CASMI 2016 contest. RESULTS: The results on the 87 MS/MS spectra from positive and negative mode show a substantial improvement of the results compared to submissions made by the former MetFrag approach. Top1 rankings increased from 5 to 21 and Top10 rankings from 39 to 55 both showing higher values than for CSI:IOKR, the winner of the CASMI 2016 contest. For the negative mode spectra, MetFrag's statistical scoring outperforms all other participants which submitted results for this type of spectra. CONCLUSIONS: This study shows how statistical learning can improve molecular structure identification based on MS/MS data compared on the same method using combinatorial in silico fragmentation only. MetFrag2.4.5 shows especially in negative mode a better performance compared to the other participating approaches. PMID: 31277571 [PubMed - in process]

Related Articles Metabolic Plasticity and Epithelial-Mesenchymal Transition. J Clin Med. 2019 Jul 03;8(7): Authors: Thomson TM, Balcells C, Cascante M Abstract A major transcriptional and phenotypic reprogramming event during development is the establishment of the mesodermal layer from the ectoderm through epithelial-mesenchymal transition (EMT). EMT is employed in subsequent developmental events, and also in many physiological and pathological processes, such as the dissemination of cancer cells through metastasis, as a reversible transition between epithelial and mesenchymal states. The remarkable phenotypic remodeling accompanying these transitions is driven by characteristic transcription factors whose activities and/or activation depend upon signaling cues and co-factors, including intermediary metabolites. In this review, we summarize salient metabolic features that enable or instigate these transitions, as well as adaptations undergone by cells to meet the metabolic requirements of their new states, with an emphasis on the roles played by the metabolic regulation of epigenetic modifications, notably methylation and acetylation. PMID: 31277295 [PubMed]

Related Articles Effects of Water Availability in the Soil on Tropane Alkaloid Production in Cultivated Datura stramonium. Metabolites. 2019 Jul 03;9(7): Authors: Moreno-Pedraza A, Gabriel J, Treutler H, Winkler R, Vergara F Abstract BACKGROUND: different Solanaceae and Erythroxylaceae species produce tropane alkaloids. These alkaloids are the starting material in the production of different pharmaceuticals. The commercial demand for tropane alkaloids is covered by extracting them from cultivated plants. Datura stramonium is cultivated under greenhouse conditions as a source of tropane alkaloids. Here we investigate the effect of different levels of water availability in the soil on the production of tropane alkaloids by D. stramonium. METHODS: We tested four irrigation levels on the accumulation of tropane alkaloids. We analyzed the profile of tropane alkaloids using an untargeted liquid chromatography/mass spectrometry method. RESULTS: Using a combination of informatics and manual interpretation of mass spectra, we generated several structure hypotheses for signals in D. stramonium extracts that we assign as putative tropane alkaloids. Quantitation of mass spectrometry signals for our structure hypotheses across different anatomical organs allowed us to identify patterns of tropane alkaloids associated with different levels of irrigation. Furthermore, we identified anatomic partitioning of tropane alkaloid isomers with pharmaceutical applications. CONCLUSIONS: Our results show that soil water availability is an effective method for maximizing the production of specific tropane alkaloids for industrial applications. PMID: 31277288 [PubMed]

23 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/07/06PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

23 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/07/06PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Small Molecular Modulators of JMJD1C Preferentially Inhibit Growth of Leukemia Cells. Int J Cancer. 2019 Jul 04;: Authors: Xu X, Wang L, Hu L, Dirks WG, Zhao Y, Wei Z, Chen D, Li Z, Wang Z, Han Y, Wei L, Drexler HG, Hu Z Abstract Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia (MLLr AL). Here we focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. JMJD1C Jumomji domain inhibitor 4 (JDI-4) and JDI-12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI-4 and JDI-12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI-4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI-4 and JDI-12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI-4 and JDI-12 kill MLLr AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI-16, among multiple compounds structurally akin to JDI-4/JDI-12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI-4/JDI-12. Mechanistically, JDI-16 not only induces apoptosis but also differentiation of MLLr AL cells. RNA sequencing and quantitative PCR showed that JDI-16 induced gene expression associated to cell metabolism; targeted metabolomics revealed that JDI-16 downregulates lactic acids, NADP+ and other metabolites. Moreover, JDI-16 collaborates with all-trans retinoic acid to repress MLLr AML cells. In summary, we identified bona fide JMJD1C inhibitors that induce preferential death of MLLr AL cells. This article is protected by copyright. All rights reserved. PMID: 31271662 [PubMed - as supplied by publisher]

Changes in whole metabolites after exenatide treatment in overweight/obese polycystic ovary syndrome patients. Clin Endocrinol (Oxf). 2019 Jul 04;: Authors: Tang L, Yuan L, Yang G, Wang F, Fu M, Chen M, Liu D Abstract OBJECTIVE: Exenatide is a new agent for diabetes therapy, and its use in polycystic ovary syndrome (PCOS) has gradually increased; however, the clinical benefit and metabolic improvement need further evidence. This research aimed to study the changes in whole metabolites before and after exenatide treatment in overweight/obese PCOS patients to gain a better understanding of exenatide for the treatment of PCOS. METHODS: Sixty-seven women, including 32 with PCOS and 35 age-matched controls, were recruited. The metabolite changes were detected with non-targeted gas chromatography tandem mass spectrometry (NTGC-MS) before and after exenatide treatment, and changes in clinical biochemical characteristics were also observed. RESULTS: A total of 62 metabolites were differentially expressed between the healthy and PCOS groups, and 31 differentially expressed metabolites were detected before and after exenatide treatment. Abnormal lipid metabolism and amino acid metabolism were the main metabolic disorders. Exenatide improved lipid and amino acid metabolism, especially amino acid metabolites. Three types of branched-chain amino acids (valine, leucine, and isoleucine), two types of aromatic amino acids (phenylalanine and tyrosine) and lysine are important potential metabolites for the therapeutic efficacy of exenatide. Many abnormal metabolic disorders are related to insulin resistance, oxidative stress, and even ovulatory dysfunction. Moreover, in this small sample clinical study, we also found that exenatide improved insulin sensitivity, reduced body weight and improved glycolipid metabolism in PCOS. CONCLUSIONS: NTGC-MS-based metabolic pathway analysis revealed that exenatide has a beneficial effect on overweight/obese PCOS patients by regulating metabolic disorders, especially amino acid disorders. This article is protected by copyright. All rights reserved. PMID: 31271659 [PubMed - as supplied by publisher]

Can Galactose Be Converted To Glucose In HepG2 Cells? - Improving the in vitro Mitochondrial Toxicity Assay for the Assessment of Drug Induced Liver Injury. Chem Res Toxicol. 2019 Jul 04;: Authors: Xu Q, Liu L, Vu H, Kuhls M, Aslamkhan AG, Liaw A, Yu Y, Kaczor A, Ruth M, Wei C, Imredy J, Lebron J, Pearson K, Gonzalez R, Mitra K, Sistare F Abstract Human hepatocellular carcinoma cells, HepG2, are often used for drug mediated mitochondrial toxicity assessments. Glucose in HepG2 culture media is replaced by galactose to reveal drug-induced mitochondrial toxicity as a marked shift of drug IC50 values for the reduction of cellular ATP. It has been postulated that galactose sensitizes HepG2 mitochondria by the additional ATP consumption demand in the Leloir pathway, which describes the galactose→glucose conversion. However, our NMR metabolomics analysis of HepG2 cells and culture media showed very limited, if any, galactose metabolism. To clarify the role of galactose in HepG2 cellular metabolism, U-13C6-galactose or U-13C6-glucose was added to HepG2 culture media to help specifically track the metabolism of those two sugars. No conversion to U-13C3-lactate was detected when HepG2 cells were incubated with U-13C6-galactose, while an abundance of U-13C3-lactate was produced when HepG2 cells were incubated with U-13C6-glucose. In the absence of glucose, HepG2 cells increased glutamine consumption as a bioenergetics source. Requirement of additional glutamine matched the amount of glucose needed to maintain a steady level of cellular ATP in HepG2 cells. This improved understanding of galactose and glutamine metabolism in HepG2 cells helped optimize the ATP based mitochondrial toxicity assay. The modified assay showed 96% sensitivity and 97% specificity in correctly discriminating compounds known to cause mitochondrial toxicity from those with prior evidences of not being mitochondrial toxicants. The greatest significance of the modified assay was its improved sensitivity in detecting the inhibition of mitochondrial fatty acid β-oxidation (FAO) when glutamine was withheld. By eliminating glutamine, the assay was able to differentially identify inhibitors of FAO and mitochondrial complex II from those of other mitochondrial complexes. Use of this improved assay for an empirical prediction of the likely contribution of mitochondrial toxicity to human DILI (drug induced liver injury) was attempted. Testing of 120 DILI positive and negative compounds representing numerous mechanisms of DILI, the overall prediction of mitochondrial mechanism-related DILI showed 25% sensitivity and 95% specificity. PMID: 31271030 [PubMed - as supplied by publisher]

Related Articles Multiple metabolic pathways are predictive of ricin intoxication in a rat model. Metabolomics. 2019 Jul 03;15(7):102 Authors: D'Elia RV, Goodchild SA, Winder CL, Southam AD, Weber RJM, Stahl FM, Docx C, Patel V, Green AC, Viant MR, Lukaszewski RA, Dunn WB Abstract INTRODUCTION: Exposure to ricin can be lethal and treatments that are under development have short windows of opportunity for administration after exposure. It is therefore essential to achieve early detection of ricin exposure to provide the best prognosis for exposed individuals. Ricin toxin can be detected in clinical samples via several antibody-based techniques, but the efficacy of these can be limited due to the rapid processing and cellular uptake of toxin in the body and subsequent low blood ricin concentrations. Other diagnostic tools that perform, in an orthogonal manner, are therefore desirable. OBJECTIVES: To determine time-dependent metabolic changes in Sprague-Dawley rats following intravenous exposure to ricin. METHODS: Sprague-Dawley rats were intravenously exposed to ricin and multiple blood samples were collected from each animal for up to 48 h following exposure in two independent studies. Plasma samples were analysed applying HILIC and C18 reversed phase UHPLC-MS assays followed by univariate and multivariate analysis. RESULTS: In Sprague-Dawley rats we have demonstrated that metabolic changes measured in blood can distinguish between rats exposed intravenously to ricin and controls prior to the onset of behavioral signs of intoxication after 24 h. A total of 37 metabolites were significantly altered following exposure to ricin when compared to controls. The arginine/proline, bile acid and triacylglyceride metabolic pathways were highlighted as being important with two triacylglycerides at 8 h post exposure giving an AUROC score of 0.94. At 16 h and 24 h the AUROC score increased to 0.98 and 1.0 with the number of metabolites in the panel increasing to 5 and 7, respectively. CONCLUSIONS: These data demonstrate that metabolites may be a useful tool to diagnose and detect ricin exposure, thus increasing the effectiveness of supportive therapy and future ricin-specific medical treatments. PMID: 31270703 [PubMed - in process]

Related Articles Differential metabolic responses of shrubs and grasses to water additions in arid karst region, southwestern China. Sci Rep. 2019 Jul 03;9(1):9613 Authors: Umair M, Sun N, Du H, Yuan J, Abbasi AM, Wen J, Yu W, Zhou J, Liu C Abstract Increasing precipitation has been predicted to occur in the karst areas in southwestern regions of China. However, it is little known how various plants respond to increasing precipitation in this region. Here we determined the impacts of water addition on leaf metabolites of grasses (Cymbopogon distans and Arundinella sitosa) and shrubs (Carissa spinarum and Bauhinia brachycarpa) in this area. Four levels of water additions (CK, T1, T2 and T3 indicating 0%, +20%, +40% and +60% relative to the current monthly precipitation, respectively) were designed. Sphingolipids substantially increased in the leaves of all four species with increasing water supply which suggests that these plants adopted biochemical strategy to tolerate the wet stress. However, both shrubs showed decreases in valine and threonine (amino acids), threonate, succinate and ascorbic acid (organic acids), galactose and rhamnose (sugars) and epicatchin and oleamides (secondary metabolites) with increasing water supply. Both grasses increased in the total metabolites at T1, but the total metabolites in A. sitosa significantly decreased at T2 and T3 while remains unchanged in C. distans. Tri-carboxylic acid cycle and amino acid metabolism in shrubs and shikimate pathway in grasses were strongly affected with water supply. Overall, shrubs and grasses respond differentially to variation in water addition in terms of metabolomics, which is helpful in understanding how plants respond to climate change. PMID: 31270427 [PubMed - in process]